PROJECT SUMMARY/ABSTRACT The long-term goal of this project is to develop novel targeted therapies for T-cell acute lymphoblastic leukemia (T-ALL). T-ALL is an aggressive hematologic malignancy that comprises 15% of pediatric ALL and 25% of adult-ALL. Current treatment consists of intense chemotherapy that is associated with acute and chronic life-threatening or debilitating toxicities. Five-year event-free survival is 70-75% for children, 30-40% for adults under 60, and less than 10% for adults over age 60. The prognosis after relapse is dismal, with 3 year event-free survival of only 10-15%. There is compelling evidence that increased MYC activity is central to the pathogenesis of most cases of T-ALL. Although MYC is a potent oncogene, it has an Achilles heel. In addition to providing a proliferative signal, MYC strongly induces apoptosis, in part, through an ARF/MDM2/TP53 pathway. Indeed, without additional mutations/signals which inactivate apoptosis, increased MYC expression is not sufficient to induce leukemia/lymphoma. In T-ALL, this second signal is likely homozygous inactivating mutations of CDKN2A encoding p14 (ARF), which are present in ~80% of T-ALL. Together, these data support the hypothesis that agents that target MYC-associated survival pathways will be selectively toxic to T-ALL cells. CXCR4 is by far the most highly expressed chemokine receptor expressed on T-ALL cells, and there is evidence that CXCL12, through interaction with CXCR4, provides a key survival signal for T-ALL cells. Thus, we hypothesize that CXCR4 blockade may have therapeutic activity in T-ALL. Consistent with this hypothesis, our preliminary and published preclinical data show that T-ALL cells are exquisitely sensitive to CXCR4 inhibition. The following specific aims are proposed to test these hypotheses. Aim 1. To test the combination of BL-8040 and nelarabine in adults with relapsed/refractory T- ALL/lymphoblastic lymphoma. Aim 2. To develop novel therapeutic strategies that target the dependence of T-ALL on MYC-signaling.